Efforts to develop beta-lactam antibiotics, i.e., penicillins and cephalosporins, having improved efficacy, particularly against gram-negative and beta-lactam resistant organisms, have progressed along several paths. The first is directed to chemical modification of the substituent groups on the basic penam or cepham nucleus, especially of the amino groups at the 6- and 7-positions, respectively, of said nuclei. A second path is aimed at modification of the basic beta-lactam nuclei of said antibiotics. More recently, attention has focused on physical and chemical combinations of a beta-lactam antibiotic with a beta-lactamase inhibitor; i.e., a substance which inhibits beta-lactamases and, as a result, prevents their degrading the beta-lactam ring of said antibiotics to products devoid of antibacterial activity.
Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo and useful as antibacterial agents and beta-lactamase inhibitors are disclosed in U.S. Pat. No. 4,234,579, issued Nov. 18, 1980.
Bis-esters of alkanediols with penicillins and penicillanic acid 1,1-dioxide useful, because of their tendency to hydrolyze in vivo to provide both a penicillin and a beta-lactamase inhibitor, as antibacterial agents against beta-lactamase producing bacteria are described in U.S. Pat. No. 4,244,951, issued Jan. 13, 1981, and in British Pat. Application 2,044,255A, published Oct. 15, 1980. U.S. Pat. No. 4,364,957, issued Dec. 21, 1982 describes bis-esters of alkanediols with 6-acyl amidopenicillanic acid and 2-beta-acetoxymethyl-2-alpha-methyl-(5R)penam-3-alpha-carboxylic acid 1,1-dioxide as antibacterial agents. In U.S. Pat. No. 4,342,772 issued Aug. 3, 1982, analogous compounds are disclosed in which penicillins and beta-lactamase inhibitors such as penicillanic acid 1,1-dioxide, clavulanic acid and 6-beta-halopenicillanic acids are linked via 1,1-alkanediol groups.
In copending application Ser. No. 407,540, filed Aug. 12, 1982 and assigned to the same assignee, there are described bis-esters of methanediol in which one hydroxy group is esterified with the carboxy group of a beta-lactamase inhibitor and the other with the carboxy group of an O-acyl derivative of amoxicillin.
Bis-esters of 1,1-alkanediols with 6-beta-hydroxymethylpenicillanic acid 1,1-dioxide are disclosed in U.S. Pat. No. 4,342,768. The corresponding derivatives of 6-alpha-hydroxymethylpenicillanic acid 1,1-dioxide are disclosed in copending application Ser. No. 338,794, filed Jan. 11, 1982, assigned to the same assignee. 6-Aminoalkyl penicillanic acid 1,1-dioxide beta-lactamase inhibitors are disclosed in copending application Ser. No. 434,731, filed Oct. 21, 1982 and assigned to the same assignee.
U.S. Pat. No. 4,377,590, issued Mar. 22, 1983 describes derivatives of methanediol with a betalactamase inhibitor, e.g. sulbactam or its 6-hydroxymethyl derivative, and amoxicillin, the latter being linked through its phenolic group. Amoxicillin, 6-[D-(2-amino-2-[p-hydroxyphenyl]acetamido)]penicillanic acid is known from U.S. Pat. No. 3,192,198 and 28,744. p-Acyl derivatives of amoxicillin are disclosed in U.S. Pat. Nos. 2,985,648, and 3,520,876.